The underlying mechanism of opiates involves N-type (CaV2.2) Ca2+ channels that drive synaptic transmission and thereby convey pain impulses to the central nervous system. The effects of opiates are then produced in substantial measure by receptor activation of G proteins that inhibit these very channels. N-type Ca2+ channels figure prominently in conveying this sensory modality, and the renowned analgesia of opiates is produced in large measure via receptor activation of Gβγ to inhibit these channels. Classic opiates like morphine produce tolerance and threaten addiction at therapeutic doses, so adjunct strategies have been devised, such as toxin inhibition of N-type channels. Still, such alternate approaches also incur serious side effects. In the context of pain, known drug therapies have utility, but there are serious drawbacks to their use. Many existing drugs also have substantial adverse side effects in certain subjects leading to careful and expensive monitoring. Additionally, most existing drugs bring only temporary relief to sufferers and must be taken consistently on a daily or weekly basis for continued relief and with disease progression, the amount of medication needed to alleviate the pain may increase thus increasing the potential for side effects.
Genetic or pharmacological perturbations in ion channel function can have dramatic clinical consequences and toxic side affects such as arrhythmia and seizure which are triggered by certain drugs are due to interference with ion channel function. Thus, there is still a need for an effective and safe treatment to alleviate pain and to produce analgesia and for pharmaceutical compositions useful for the therapeutic modulation of ion channel activity and methods for developing such methods that have applications in treatment of many pathological conditions.